Cohen Syndrome

Cohen syndrome is a rare genetic condition that affects many parts of the body, including physical growth, vision, and learning abilities. Children with this condition usually experience delays in reaching developmental milestones like rolling over, sitting, walking, and talking. They often have weak muscle tone (hypotonia) as babies, which can cause feeding difficulties. As they grow, they typically develop a smaller-than-average head size, joint flexibility, and a specific pattern of weight gain where they become heavier around the middle (truncal obesity) while keeping slender arms and legs. Vision problems are a major part of Cohen syndrome. Most individuals develop severe nearsightedness (myopia) that gets worse over time. They also experience a condition called retinal dystrophy, which damages the light-sensitive tissue at the back of the eye. This can lead to night blindness, clumsiness due to poor peripheral vision, and a gradual decline in eyesight, though complete blindness is uncommon. Regular eye exams are crucial to monitor and manage these changes. People with Cohen syndrome often have a very friendly, cheerful, and sociable personality. They may also have lower levels of certain white blood cells (neutropenia), which can make them more prone to frequent infections like ear infections or mouth sores. While there is no cure for Cohen syndrome, early intervention with physical, occupational, and speech therapies, along with special education support and regular medical care, can greatly help manage symptoms and improve quality of life.

Condition category: Syndromic IRD

Prevalence: 1 in 100,000

Inheritance patterns: Autosomal Recessive

Age of onset: Birth to early childhood

Clinical overview: Cohen syndrome is a rare, multisystemic autosomal recessive disorder characterized by a distinct combination of clinical features. The core manifestations include developmental delay, moderate-to-profound intellectual disability, early-onset hypotonia, acquired microcephaly, and characteristic facial dysmorphism. Ophthalmic involvement is a hallmark of the disease, presenting as progressive high myopia and retinal dystrophy, which typically manifests as night blindness and visual field constriction. The facial gestalt of Cohen syndrome is distinctive, featuring thick scalp hair, a low posterior hairline, thick eyebrows, long eyelashes, wave-shaped palpebral fissures, a broad nasal tip, a short philtrum, and prominent upper central incisors, which often result in an open-mouth appearance. These features become more pronounced as the child ages, typically becoming obvious by age 9. Metabolic and hematologic abnormalities are also prominent. Patients often experience poor weight gain in infancy followed by the development of truncal obesity in mid-childhood, despite slender extremities. Neutropenia, which can be mild to moderate, is a consistent finding and may predispose patients to recurrent infections, such as otitis media and aphthous ulcers. Despite the significant cognitive and physical challenges, individuals with Cohen syndrome are frequently described as having a cheerful and sociable disposition.

Patient and family guide: Cohen syndrome is a rare genetic condition that affects many parts of the body, including physical growth, vision, and learning abilities. Children with this condition usually experience delays in reaching developmental milestones like rolling over, sitting, walking, and talking. They often have weak muscle tone (hypotonia) as babies, which can cause feeding difficulties. As they grow, they typically develop a smaller-than-average head size, joint flexibility, and a specific pattern of weight gain where they become heavier around the middle (truncal obesity) while keeping slender arms and legs. Vision problems are a major part of Cohen syndrome. Most individuals develop severe nearsightedness (myopia) that gets worse over time. They also experience a condition called retinal dystrophy, which damages the light-sensitive tissue at the back of the eye. This can lead to night blindness, clumsiness due to poor peripheral vision, and a gradual decline in eyesight, though complete blindness is uncommon. Regular eye exams are crucial to monitor and manage these changes. People with Cohen syndrome often have a very friendly, cheerful, and sociable personality. They may also have lower levels of certain white blood cells (neutropenia), which can make them more prone to frequent infections like ear infections or mouth sores. While there is no cure for Cohen syndrome, early intervention with physical, occupational, and speech therapies, along with special education support and regular medical care, can greatly help manage symptoms and improve quality of life.

Symptoms and clinical features: Symptoms of Cohen syndrome present early in life with hypotonia, feeding difficulties, and delayed motor and speech milestones. Microcephaly develops during or after the first year. Children exhibit joint hypermobility and a clumsy gait. Ophthalmologic symptoms include progressive high myopia, astigmatism, and strabismus. Retinal dystrophy causes night blindness (nyctalopia) and constricted peripheral vision, leading to frequent tripping. Physical features include short stature and truncal obesity that develops rapidly in mid-childhood. Characteristic facial features include thick hair, wave-shaped eyes, a short philtrum, and prominent upper teeth. Hematologic symptoms include neutropenia, which can lead to recurrent infections such as otitis media, pneumonia, and aphthous ulcers. Behaviorally, patients have moderate-to-profound intellectual disability but typically display a cheerful, friendly, and sociable disposition.

Molecular pathology: Cohen syndrome is caused by biallelic mutations in the VPS13B gene (formerly known as COH1), located on chromosome 8q22.2. Over 660 pathogenic variants have been identified, mostly truncating loss-of-function mutations. The VPS13B gene encodes a large peripheral membrane protein that is part of the bridge-like lipid transport (BLTP) protein family. The VPS13B protein predominantly localizes to the Golgi apparatus and is essential for the maintenance of organelle architecture. It is proposed to act as a lipid transport protein at organellar membrane contact sites, potentially facilitating lipid transfer through a hydrophobic tunnel between adjacent membranes. It may also play a role in Golgi retrograde trafficking and is involved in the glycosylation of proteins. A prominent cellular defect observed in VPS13B-depleted cells is Golgi fragmentation. The functional impairment of the Golgi apparatus leads to protein glycosylation defects, which have been observed in serum samples from Cohen syndrome patients. The exact mechanism by which VPS13B dysfunction leads to the diverse clinical manifestations of Cohen syndrome, including retinal dystrophy, microcephaly, and neutropenia, is not fully understood, but it is likely related to the disruption of intracellular lipid transport, membrane homeostasis, and vesicular trafficking.

Genetics: Cohen syndrome is inherited in an autosomal recessive pattern. This means an affected individual must inherit two copies of the mutated VPS13B gene, one from each parent. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene but typically do not show signs and symptoms of the condition. Penetrance is complete, meaning all individuals with biallelic pathogenic variants will show some features of the condition, but expressivity is highly variable. The severity of developmental delay, intellectual disability, and other clinical features can vary considerably, even among affected siblings. Genetic counseling is recommended for affected individuals and their families. If both parents are known to be carriers of a VPS13B pathogenic variant, each pregnancy has a 25% chance of resulting in an affected child, a 50% chance of resulting in a carrier child, and a 25% chance of resulting in an unaffected, non-carrier child. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Diagnostic evaluation: Diagnosis of Cohen syndrome is established in a proband with suggestive clinical findings and the identification of biallelic pathogenic variants in the VPS13B gene by molecular genetic testing. Clinical diagnosis is suspected based on developmental delay, hypotonia, microcephaly, characteristic facial features (thick hair, wave-shaped palpebral fissures, prominent upper central incisors), truncal obesity, progressive high myopia, and retinal dystrophy. Neutropenia is also a key diagnostic marker. Ophthalmic examination including electroretinogram (ERG) is crucial for identifying retinal dystrophy, which may show changes even in young children. Blood tests are used to detect neutropenia. Genetic testing confirms the diagnosis.

Differential diagnosis: Prader-Willi syndrome, Bardet-Biedl syndrome, Alström syndrome, Cri-du-chat syndrome, Angelman syndrome, Williams syndrome, Mirhosseini-Holmes-Walton syndrome

Natural history: The natural history of Cohen syndrome begins in infancy with hypotonia, feeding difficulties, and delayed developmental milestones. Microcephaly usually develops during or after the first year of life. In early childhood, patients often present with a cheerful disposition and joint laxity. Progressive high myopia typically becomes apparent around age 4.5 years. Retinal dystrophy, indicated by defective dark adaptation or night blindness, is usually noticed after age 7, though ERG changes can be seen earlier. The retinal degeneration progresses over time, often leading to constricted visual fields and bull's-eye maculopathy, but complete blindness is rare. Truncal obesity typically develops in mid-childhood, with an average onset around 11 years, characterized by rapid weight gain. Characteristic facial features become more prominent by age 9. Neutropenia is present throughout life and may lead to recurrent infections. Cognitive abilities do not regress, but individuals generally require lifelong assistance.

Management and treatment research: ### Current Management and Supportive Care There is currently no cure for Cohen syndrome. Care focuses on managing symptoms, supporting development and independence, and monitoring for health concerns. Care is often coordinated among primary care, medical genetics, ophthalmology, hematology, developmental specialists, therapists, nutrition professionals, and dental professionals. - **Developmental and educational support:** Early-intervention services, including physical therapy, occupational therapy, and speech-language therapy, may help with low muscle tone (hypotonia), delayed motor development, communication needs, and daily-living skills. Individualized education programs and other school supports can be helpful for people with intellectual disability or learning differences. - **Eye care and low-vision support:** Retinal dystrophy and high myopia (severe nearsightedness) are common and can cause progressive vision loss. Regular examinations with an ophthalmologist—ideally one familiar with inherited retinal diseases—are important. Care may include prescription glasses or contact lenses, low-vision rehabilitation, assistive technology, orientation and mobility training, and school or workplace accommodations. Some people develop cystoid macular edema, a buildup of fluid in the central retina. An eye specialist may consider a carbonic anhydrase inhibitor, such as dorzolamide eye drops, and monitor whether it reduces retinal swelling. - **Neutropenia and infection care:** Neutropenia is a low level of neutrophils, a type of white blood cell that helps fight bacterial infections. Regular blood-count monitoring may be recommended. Fever or suspected infection should be evaluated promptly. For recurrent serious infections, severe mouth ulcers, or persistent clinically significant neutropenia, a hematology specialist may consider granulocyte colony-stimulating factor (G-CSF), which stimulates neutrophil production. - **Other routine care:** Ongoing dental care, nutritional assessment, monitoring for scoliosis or joint concerns, and behavioral or mental-health support may be part of an individualized care plan. ### Approved Therapies There are no FDA-approved treatments that address the underlying genetic cause of Cohen syndrome or reverse its retinal degeneration. ### Investigational Therapies and Research Cohen syndrome is most often caused by disease-causing variants in the **VPS13B** gene. VPS13B is involved in normal cell organization and protein transport, including functions related to the Golgi apparatus, a cell structure that processes and moves proteins. No Cohen syndrome–specific investigational treatments are currently listed in the available treatment pipeline. This includes no active VPS13B-targeted gene therapies, RNA-based therapies, cell therapies, or targeted medicines for the retinal disease associated with Cohen syndrome. Research on VPS13B-associated disease remains important for understanding effects on the retina, immune system, development, and other body systems. Natural-history studies, which follow how a condition changes over time, may help prepare for future treatment development. ### Clinical Trial Participation No active clinical trials specifically studying Cohen syndrome or VPS13B-related retinal disease are identified in the current trial data. The listed studies are for unrelated conditions, including cancers, schizophrenia, post-traumatic stress disorder, and POLG disease; they are not Cohen syndrome treatment studies. Families interested in research opportunities can ask their genetics, ophthalmology, or hematology team about patient registries, natural-history studies, and future research related to **VPS13B** and Cohen syndrome.

Outlook: The prognosis for individuals with Cohen syndrome is generally stable, as the condition is not life-threatening and most individuals have a normal life expectancy. However, they will require lifelong assistance and support due to moderate-to-profound intellectual disability. Vision progressively worsens due to high myopia and retinal dystrophy, leading to significant visual impairment, though complete blindness is rare. Recurrent infections due to neutropenia can impact quality of life but are usually manageable. With appropriate therapies and educational support, individuals can lead fulfilling lives, aided by their typically cheerful and sociable disposition.

Epidemiology: Cohen syndrome is a rare genetic disorder with an estimated prevalence of approximately 1 in 100,000, though it may be underdiagnosed. It has been diagnosed in fewer than 1,000 people worldwide, but projections based on gnomAD database variants suggest it could affect up to 50,000 individuals globally. The condition is overrepresented in certain populations due to founder effects, particularly in the Finnish population, as well as in Amish, Greek (Mediterranean), and Irish ancestries. It affects both males and females equally.

Selected references: 1. Kolehmainen J, et al. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet. 2003. 2. Wang H, et al. Cohen Syndrome. GeneReviews. 2006 (Updated 2021). 3. Kivitie-Kallio S, Norio R. Cohen syndrome: essential features, natural history, and heterogeneity. Am J Med Genet. 2001. 4. Vacca F, et al. Exploring the pathological mechanisms underlying Cohen syndrome. Front Neurosci. 2024. 5. Güneş N, et al. Early Diagnostic Signs and the Natural History of Typical Findings in Cohen Syndrome. Pediatrics. 2023.